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MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP.

Yahui YanCláudia RatoLukas RohlandSteffen PreisslerDavid Ron
Published in: Nature communications (2019)
Despite its known role as a secreted neuroprotectant, much of the mesencephalic astrocyte-derived neurotrophic factor (MANF) is retained in the endoplasmic reticulum (ER) of producer cells. There, by unknown mechanisms, MANF plays a role in protein folding homeostasis in complex with the ER-localized Hsp70 chaperone BiP. Here we report that the SAF-A/B, Acinus, and PIAS (SAP) domain of MANF selectively associates with the nucleotide binding domain (NBD) of ADP-bound BiP. In crystal structures the SAP domain engages the cleft between NBD subdomains Ia and IIa, stabilizing the ADP-bound conformation and clashing with the interdomain linker that occupies this site in ATP-bound BiP. MANF inhibits both ADP release from BiP and ATP binding to BiP, and thereby client release. Cells lacking MANF have fewer ER stress-induced BiP-containing high molecular weight complexes. These findings suggest that MANF contributes to protein folding homeostasis as a nucleotide exchange inhibitor that stabilizes certain BiP-client complexes.
Keyphrases
  • endoplasmic reticulum
  • stress induced
  • induced apoptosis
  • molecular dynamics simulations
  • binding protein
  • single molecule
  • heat shock
  • protein protein
  • estrogen receptor
  • cell death
  • dna binding